NOTCH3蛋白及GOM对CADASIL发病机制作用的研究
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摘要
第一章NOTCH3基因突变的研究
目的通过对临床拟诊伴皮层下梗死和白质脑病的常染色体显性遗传性脑动脉病(CADASIL)患者进行NOTCH3基因的2-23外显子突变检测,对疾病作出基因诊断。
方法采用DNA直接测序方法对25例临床拟诊CADASIL先证者进行NOTCH3基因的2-23外显子突变检测；并对已发现突变的先证者8个家系成员共116人,进行突变外显子检测；正常对照组100样本进行NOTCH3基因测序。
结果①发现9例NOTCH3基因突变(35%),突变分别分别位于第3外显子的R90C,第4外显子的R133C、R153C、C185Y、R182C(2例)、R133S及第11外显子的R544C(2例),均为错义点突变。②第4外显子的R133S突变是一种新的保留半胱氨酸的NOTCH3基因突变。③1例散发患者存在位于第4外显子的R182C突变。
结论①首次报道4外显子的R133S突变是一种新的保留半胱氨酸的NOTCH3基因突变。②国内首次报道1例散发患者存在第4外显子的R182C突变。
第二章NOTCH3蛋白及GOM对CADASIL诊断价值的研究
目的探讨KLH法制备的NOTCH3氨基端(N)多克隆抗体及GOM对CADASIL诊断价值。
方法应用人工合成NOTCH3氨基端(N)一个多肽片段,通过KLH方法制备全新NOTCH3N-末端多克隆抗体,通过纯化后、经ELISA法及Western blot证实得到的抗体为抗NOTCH3N-末端的特异抗体。31例CADASIL患者及25例匹配的非CADASIL对照患者分别行皮肤活检,通过电子显微镜观察血管超微结构改变,并评估其超微结构GOM沉积,以及NOTCH3N-末端多克隆抗体的免疫组化方法的敏感性和特异性。
结果①成功的制作了NOTCH3N-末端多克隆抗体。②31例患者的皮肤血管超微结构表现：大多数血管壁增厚,颗粒样嗜锇性物质主要沉积在小动脉和小静脉血管平滑肌细胞表面,偶尔位于毛细血管内皮细胞周围。血管平滑肌细胞和内皮细胞变性,它们细胞质中充满许多嗜锇性物质小泡以及线粒体空泡样变性。25例对照中仅1例老年人中偶见血管基底膜增厚。③31例CADASIL患者超微结构GOM沉积的敏感性为54.5%,特异性为96%；而用NOTCH3N-末端多克隆抗体的免疫组化方法的敏感性为75.7%,特异性为98%；将两种方法结合其敏感性为91%,特异性为97%。
结论这种全新的NOTCH3N-末端特异性抗体的免疫组化方法结合电镜超微结构GOM能有效提高CADASIL确诊率。
第三章NOTCH3蛋白与GOM关系的研究
目的探讨NOTCH3蛋白与GOM两者之间关系。揭示GOM的生物化学特性和来源。
方法应用人工合成NOTCH3氨基端(N)及NOTCH3羧端(C)两个多肽片段,通过KLH方法制备抗NOTCH3N-末端多克隆抗体和NOTCH3C-末端多克隆抗体,纯化后、经ELISA法及Western blot证实得到的两个抗体均为特异抗体。9例CADASIL患者及25例匹配的非CADASIL对照患者分别行皮肤活检,其中2例CADASIL患者行脑组织活检,而2例非CADASIL患者脑组织作为对照,利用免疫电子显微镜技术揭示GOM与NOTCH3受体外侧和内侧结构域的关系。
结果①成功的制备NOTCH3N-末端多克隆抗体和NOTCH3C-末端多克隆抗体。②CADASIL患者脑组织和皮肤血管平滑肌细胞表面均有GOM和NOTCH3N-末端抗体特异的胶体金颗粒沉积,无NOTCH3C-末端抗体特异的胶体金颗粒沉积；这些NOTCH3N-末端抗体特异的胶体金颗粒沉积邻近GOM,或位于GOM内。③对照组中未发现GOM的沉积及NOTCH3抗体胶体金颗粒沉积。
结论GOM的主要成分可能为NOTCH3受体外侧结构域,揭示GOM生物学特性和它与NOTCH3基因的关系,为进一步揭示CADASIL的病理机理提供新的研究思路。
Part 1 NOTCH3 gene mutation
Objective:To make the gene diagnosis through analyzing the mutation on exon 2 to 23 of the NOTCH3 gene in clinical doubted cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) patients.
Methods:25 index cases of clinical doubted CADASIL were detected for the mutation on exon 2 to 23 of NOTCH3 gene. The mutation-proven probands from 8 families (totally 116 members) were mutation-detecting in exons.100 normal samples of control groups were genically sequened.
Results:①There were 9 cases of missense mutations in the NOTCH3 gene, including R90C in exon 3 in a probands, R133C, R153C, C185Y, R182C (2 cases) and R133S in exon 4, and R544C (2 cases) in exon 11.②The mutation of R133S in exon 4 is a novel NOTCH3 gene mutation of remaining cysteine, which has not been reported at home and abroad.③It hasn't been reported in China that a sporadic patient has the mutation of R182C in exon 4.
Conclusion:①The mutation of R133S in exon 4 is a novel NOTCH3 gene mutation of remaining cysteine, which has not been reported at home and abroad.②It hasn't been reported in China that a sporadic patient has the mutation of R182C in exon 4.
Part 2 Evaluation of diagnostic NOTCH3 protein and GOM in CADASIL
Objective:To probe the value of diagnose of an antibody against the amino-terminal(N) domain of the NOTCH3 receptor and the presence of specific granular osmiophilic deposits(GOM) in the reported 31 CADASIL patients who were made a definite diagnosis by genes.
Methods:Applying a fragment of inhibin subunits synthetic NOTCH3 molecule(N) made by the means of KLH to resist polyclonal antibody with the amino-terminal(N) domain of the NOTCH3 receptor and by the means of purifying and as well as the specific a NOTCH3 polyclonal antibody as the result of the verifying by ELISA and Western blot. Through the contrast of the skin biopsy between the 31 CADASIL patients and 25 same-aged ones without CADASIL, observing the micro change of structure in blood vessels, evaluating the sensibility and the specificity of the immunohistochemical method with the NOTCH3-N polyclonal antibody and the deposition of ultramicrostructure GOM
Results:①Developing the NOTCH3-N polyclonal antibody successfully.②Demonstration of ultramicrostructure in skin blood vessels of the 31 patients:The thickening of most vessel's wall, particles of osmiophilic matter mainly depositing the surface of vascular smooth muscle cells (VSMC) in arteriole and cellvenule, occasionally locating around the skin cells in blood capillary, denaturation of smooth muscle in blood vessels and of endothelial cells, denaturation of cytoplasm with full of osmiophilic matter vesicle and mitochondria vesicle, and only one old man in the 25 contrast was identified thickening of basement membrane in blood vessels occasionally.③The sensibility of the 31 patients with ultramicrostructure GOM deposit is 54.5%, speficity 96%, whereas through the means of the NOTCH3-N polyclonal antibody, sensibility is 75.7%, speficity 98%. However if connecting the two, the sensibility can reach 91%, and speficity 97%.
Conclusions:Both the sensibiliities evaluated by ultramicrostructure GOM and by the means of the NOTCH3-N polyclonal antibody being low, but the rate of diagnosis being enhanced effectively by combining the two means.
Part 3 Relationship between NOTCH3 protein and GOM
Objective:To discuss the relationship among GOM, the NOTCH3 protein and the degeneration of VSMC. Moreover, to illustrate the biochemical specificity and source of GOM,
Methods:The two peptide fragments, amino terminus (N) and carboxy terminal(C) of the artifical composition NOTCH3, by means of KLH, were applied to respectively prepare the antibody resisting NOTCH3 N-terminal polyclonal and the antibody resisting NOTCH3 C-terminal polyclonal. What's more, by verifying, ELISA and Western blot, they were confirmed to be specific antiboies. There were 9 cases of skin biopsies from 9 different CADASIL families, and among them, the two cases were brain biopsies. Comparing the skin of the 25 patients at same age without CADASIL and the brain tissue of the two patients without CADASIL and using immune electron microscope revealed the relationship between GOM together with the amino-terminal domain of the NOTCH3 receptor and its carboxy terminal domain.
Results:①The the NOTCH3-C polyclonal antibody and the NOTCH3-N polyclonal antibody were prepared successfully.②GOM deposits and the specifically colloidal gold particle deposits of the NOTCH3-N polyclonal antibody exist in the surface of VSMC of the skin and the brain tissue in CADASIL patients where specifically colloidal gold particle deposits of the NOTCH3-C polyclonal antibody doesn't. These deposits of the NOTCH3-N polyclonal antibody are next to GOM, even part of them in GOM.③In control groups, there are neither GOM deposits, nor colloidal gold particle deposits of any antibody.
Conclusion:The main components of GOM may be the amino-terminal(N) domain of the NOTCH3 receptor and illustrates the biological character of GOM and the relation of GOM and NOTCH3 gene. All of thses will provide a new way to studying pathological mechanism of CADASIL.
目的通过对临床拟诊伴皮层下梗死和白质脑病的常染色体显性遗传性脑动脉病(CADASIL)患者进行NOTCH3基因的2-23外显子突变检测,对疾病作出基因诊断。
方法采用DNA直接测序方法对25例临床拟诊CADASIL先证者进行NOTCH3基因的2-23外显子突变检测；并对已发现突变的先证者8个家系成员共116人,进行突变外显子检测；正常对照组100样本进行NOTCH3基因测序。
结果①发现9例NOTCH3基因突变(35%),突变分别分别位于第3外显子的R90C,第4外显子的R133C、R153C、C185Y、R182C(2例)、R133S及第11外显子的R544C(2例),均为错义点突变。②第4外显子的R133S突变是一种新的保留半胱氨酸的NOTCH3基因突变。③1例散发患者存在位于第4外显子的R182C突变。
结论①首次报道4外显子的R133S突变是一种新的保留半胱氨酸的NOTCH3基因突变。②国内首次报道1例散发患者存在第4外显子的R182C突变。
第二章NOTCH3蛋白及GOM对CADASIL诊断价值的研究
目的探讨KLH法制备的NOTCH3氨基端(N)多克隆抗体及GOM对CADASIL诊断价值。
方法应用人工合成NOTCH3氨基端(N)一个多肽片段,通过KLH方法制备全新NOTCH3N-末端多克隆抗体,通过纯化后、经ELISA法及Western blot证实得到的抗体为抗NOTCH3N-末端的特异抗体。31例CADASIL患者及25例匹配的非CADASIL对照患者分别行皮肤活检,通过电子显微镜观察血管超微结构改变,并评估其超微结构GOM沉积,以及NOTCH3N-末端多克隆抗体的免疫组化方法的敏感性和特异性。
结果①成功的制作了NOTCH3N-末端多克隆抗体。②31例患者的皮肤血管超微结构表现：大多数血管壁增厚,颗粒样嗜锇性物质主要沉积在小动脉和小静脉血管平滑肌细胞表面,偶尔位于毛细血管内皮细胞周围。血管平滑肌细胞和内皮细胞变性,它们细胞质中充满许多嗜锇性物质小泡以及线粒体空泡样变性。25例对照中仅1例老年人中偶见血管基底膜增厚。③31例CADASIL患者超微结构GOM沉积的敏感性为54.5%,特异性为96%；而用NOTCH3N-末端多克隆抗体的免疫组化方法的敏感性为75.7%,特异性为98%；将两种方法结合其敏感性为91%,特异性为97%。
结论这种全新的NOTCH3N-末端特异性抗体的免疫组化方法结合电镜超微结构GOM能有效提高CADASIL确诊率。
第三章NOTCH3蛋白与GOM关系的研究
目的探讨NOTCH3蛋白与GOM两者之间关系。揭示GOM的生物化学特性和来源。
方法应用人工合成NOTCH3氨基端(N)及NOTCH3羧端(C)两个多肽片段,通过KLH方法制备抗NOTCH3N-末端多克隆抗体和NOTCH3C-末端多克隆抗体,纯化后、经ELISA法及Western blot证实得到的两个抗体均为特异抗体。9例CADASIL患者及25例匹配的非CADASIL对照患者分别行皮肤活检,其中2例CADASIL患者行脑组织活检,而2例非CADASIL患者脑组织作为对照,利用免疫电子显微镜技术揭示GOM与NOTCH3受体外侧和内侧结构域的关系。
结果①成功的制备NOTCH3N-末端多克隆抗体和NOTCH3C-末端多克隆抗体。②CADASIL患者脑组织和皮肤血管平滑肌细胞表面均有GOM和NOTCH3N-末端抗体特异的胶体金颗粒沉积,无NOTCH3C-末端抗体特异的胶体金颗粒沉积；这些NOTCH3N-末端抗体特异的胶体金颗粒沉积邻近GOM,或位于GOM内。③对照组中未发现GOM的沉积及NOTCH3抗体胶体金颗粒沉积。
结论GOM的主要成分可能为NOTCH3受体外侧结构域,揭示GOM生物学特性和它与NOTCH3基因的关系,为进一步揭示CADASIL的病理机理提供新的研究思路。
Part 1 NOTCH3 gene mutation
Objective:To make the gene diagnosis through analyzing the mutation on exon 2 to 23 of the NOTCH3 gene in clinical doubted cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) patients.
Methods:25 index cases of clinical doubted CADASIL were detected for the mutation on exon 2 to 23 of NOTCH3 gene. The mutation-proven probands from 8 families (totally 116 members) were mutation-detecting in exons.100 normal samples of control groups were genically sequened.
Results:①There were 9 cases of missense mutations in the NOTCH3 gene, including R90C in exon 3 in a probands, R133C, R153C, C185Y, R182C (2 cases) and R133S in exon 4, and R544C (2 cases) in exon 11.②The mutation of R133S in exon 4 is a novel NOTCH3 gene mutation of remaining cysteine, which has not been reported at home and abroad.③It hasn't been reported in China that a sporadic patient has the mutation of R182C in exon 4.
Conclusion:①The mutation of R133S in exon 4 is a novel NOTCH3 gene mutation of remaining cysteine, which has not been reported at home and abroad.②It hasn't been reported in China that a sporadic patient has the mutation of R182C in exon 4.
Part 2 Evaluation of diagnostic NOTCH3 protein and GOM in CADASIL
Objective:To probe the value of diagnose of an antibody against the amino-terminal(N) domain of the NOTCH3 receptor and the presence of specific granular osmiophilic deposits(GOM) in the reported 31 CADASIL patients who were made a definite diagnosis by genes.
Methods:Applying a fragment of inhibin subunits synthetic NOTCH3 molecule(N) made by the means of KLH to resist polyclonal antibody with the amino-terminal(N) domain of the NOTCH3 receptor and by the means of purifying and as well as the specific a NOTCH3 polyclonal antibody as the result of the verifying by ELISA and Western blot. Through the contrast of the skin biopsy between the 31 CADASIL patients and 25 same-aged ones without CADASIL, observing the micro change of structure in blood vessels, evaluating the sensibility and the specificity of the immunohistochemical method with the NOTCH3-N polyclonal antibody and the deposition of ultramicrostructure GOM
Results:①Developing the NOTCH3-N polyclonal antibody successfully.②Demonstration of ultramicrostructure in skin blood vessels of the 31 patients:The thickening of most vessel's wall, particles of osmiophilic matter mainly depositing the surface of vascular smooth muscle cells (VSMC) in arteriole and cellvenule, occasionally locating around the skin cells in blood capillary, denaturation of smooth muscle in blood vessels and of endothelial cells, denaturation of cytoplasm with full of osmiophilic matter vesicle and mitochondria vesicle, and only one old man in the 25 contrast was identified thickening of basement membrane in blood vessels occasionally.③The sensibility of the 31 patients with ultramicrostructure GOM deposit is 54.5%, speficity 96%, whereas through the means of the NOTCH3-N polyclonal antibody, sensibility is 75.7%, speficity 98%. However if connecting the two, the sensibility can reach 91%, and speficity 97%.
Conclusions:Both the sensibiliities evaluated by ultramicrostructure GOM and by the means of the NOTCH3-N polyclonal antibody being low, but the rate of diagnosis being enhanced effectively by combining the two means.
Part 3 Relationship between NOTCH3 protein and GOM
Objective:To discuss the relationship among GOM, the NOTCH3 protein and the degeneration of VSMC. Moreover, to illustrate the biochemical specificity and source of GOM,
Methods:The two peptide fragments, amino terminus (N) and carboxy terminal(C) of the artifical composition NOTCH3, by means of KLH, were applied to respectively prepare the antibody resisting NOTCH3 N-terminal polyclonal and the antibody resisting NOTCH3 C-terminal polyclonal. What's more, by verifying, ELISA and Western blot, they were confirmed to be specific antiboies. There were 9 cases of skin biopsies from 9 different CADASIL families, and among them, the two cases were brain biopsies. Comparing the skin of the 25 patients at same age without CADASIL and the brain tissue of the two patients without CADASIL and using immune electron microscope revealed the relationship between GOM together with the amino-terminal domain of the NOTCH3 receptor and its carboxy terminal domain.
Results:①The the NOTCH3-C polyclonal antibody and the NOTCH3-N polyclonal antibody were prepared successfully.②GOM deposits and the specifically colloidal gold particle deposits of the NOTCH3-N polyclonal antibody exist in the surface of VSMC of the skin and the brain tissue in CADASIL patients where specifically colloidal gold particle deposits of the NOTCH3-C polyclonal antibody doesn't. These deposits of the NOTCH3-N polyclonal antibody are next to GOM, even part of them in GOM.③In control groups, there are neither GOM deposits, nor colloidal gold particle deposits of any antibody.
Conclusion:The main components of GOM may be the amino-terminal(N) domain of the NOTCH3 receptor and illustrates the biological character of GOM and the relation of GOM and NOTCH3 gene. All of thses will provide a new way to studying pathological mechanism of CADASIL.
引文
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